Morphine is one of the most frequently prescribed analgesics for the treatment of neuropathic pain after a spinal cord injury (SCI). Despite widespread use, there has been very little research on the secondary consequences of morphine administration in a spinal injury model. Unfortunately, our research suggests that the acute administration of morphine after SCI has secondary effects that reduce recovery of locomotor function, exacerbate neuropathic pain symptoms, and increase lesion size in the chronic phase of a contusion injury. These data underscore the need for further research on the effects of opioids in a SCI model. To address this issue, we will investigate the molecular consequences of morphine administration after a spinal contusion injury. Three aims are proposed. First, we will examine the role of spinal processes using agonists and antagonists (co-administered with intrathecal morphine) for classic and non-classic opioid receptors. In other models, three receptor systems have been implicated in the direct effects of morphine, including a) the m- opioid receptor, b) the k-opioid receptor, and c) non-classic opioid receptors on glia. The experiments proposed here aim to directly investigate the contribution of these receptor systems, and the role of 'overexcitation' of neural circuitry, in the morphine-induced attenuation of function after SCI. Our working hypothesis is that morphine produces antinociception (pain inhibition) through activation of classic m-opioid receptors on neurons. At compromised spinal loci, however, activation of k-opioid and glial non-classic opioid receptors may potentiate inflammatory responses and overexcitation, intrinsic to the acute phase of spinal injury, and undermine the plasticity of the neural system as well as increase cell death. Secondly, we aim to modulate spinal molecular changes, to protect functional recovery, while using a clinically relevant systemic route of morphine administration to produce analgesia. We hypothesize that we can block the effects of morphine at the spinal level using k-opioid receptor antagonists, or minocycline to block non-classic opioid activation of glia. We will also test the effects of overexcitation by blocking spinal NMDA receptor function with MK-801. Finally, we will identify cellular changes inherent to the contusion injury itself, and those produced though activation of classic and/or non-classic opioid receptors. For this third aim, we plan to target specific receptor systems, and use a cluster analysis to ascertain which molecular end-points co-vary with specific consequences of morphine administration. This proposal innovatively couples modern discoveries in opioid pharmacology with research on spinal cord injury. Most importantly, it will allow us to identify pharmacological interventions that block the adverse effects of opioids at a spinal level, while increasing morphine's beneficial (antinociceptive) effects after SCI.